An integrative model of the cardiac ventricular myocyte incorporating local control of Ca2+ release
An integrative model of the cardiac ventricular myocyte incorporating local control of Ca2+ release
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DOI：
10.1016/s0006-3495(02)75301-0
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发表时间：
2002-12-01
影响因子：
3.4
通讯作者：
Winslow, RL
中科院分区：
文献类型：
--
作者：
Greenstein, JL;Winslow, RL
心肌兴奋-收缩（EC）偶联的局部控制理论认为，l型Ca2+电流通过密切相关的l型Ca2+通道（LCCs）和ryanodine受体（RyRs）的局部相互作用，严格控制Ca2+从肌浆网（SR）释放。这些局部相互作用引起Ca2+诱导的Ca2+释放（CICR）平滑分级，具有高增益。在这项研究中，我们提出了一个符合局部控制理论的正常犬心室肌细胞的生物物理详细模型。模型公式以Ca2+释放单元（caru）的形式包含微观EC耦合特性的细节，其中单个肌层lcc在连接SR膜和横管膜非常接近的局部区域以随机方式与附近的ryr相互作用。caru嵌入心肌细胞的整体系统中并与之相互作用，描述离子和膜泵/交换电流、SR Ca2+摄取和随时间变化的细胞质离子浓度，形成心脏动作电位（AP）模型。该模型可以重现EC耦合的详细特性，如可变增益和梯度SR Ca2+释放，以及全细胞现象，如SR Ca2+释放对AP持续时间的调制。模拟表明，当l型Ca2+电流根据实验测量的电压和Ca2+依赖失活过程之间的平衡进行调整时，局部控制范式预测稳定的APs，在这种情况下，普通池模型变得不稳定。局部控制肌细胞模型为研究微观和宏观行为之间的相互关系提供了一种方法，这种方法在实验中是不可能的。
The local control theory of excitation-contraction (EC) coupling in cardiac muscle asserts that L-type Ca2+ current tightly controls Ca2+ release from the sarcoplasmic reticulum (SR) via local interaction of closely apposed L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs). These local interactions give rise to smoothly graded Ca2+-induced Ca2+ release (CICR), which exhibits high gain. In this study we present a biophysically detailed model of the normal canine ventricular myocyte that conforms to local control theory. The model formulation incorporates details of microscopic EC coupling properties in the form of Ca2+ release units (CaRUs) in which individual sarcolemmal LCCs interact in a stochastic manner with nearby RyRs in localized regions where junctional SR membrane and transverse-tubular membrane are in close proximity. The CaRUs are embedded within and interact with the global systems of the myocyte describing ionic and membrane pump/exchanger currents, SR Ca2+ uptake, and time-varying cytosolic ion concentrations to form a model of the cardiac action potential (AP). The model can reproduce both the detailed properties of EC coupling, such as variable gain and graded SR Ca2+ release, and whole-cell phenomena, such as modulation of AP duration by SR Ca2+ release. Simulations indicate that the local control paradigm predicts stable APs when the L-type Ca2+ current is adjusted in accord with the balance between voltage- and Ca2+-dependent inactivation processes as measured experimentally, a scenario where common pool models become unstable. The local control myocyte model provides a means for studying the interrelationship between microscopic and macroscopic behaviors in a manner that would not be possible in experiments.